The field of the invention relates to therapeutic peptides and prodrugs thereof. In particular, the field of the invention relates to therapeutic peptides which duplicate some of the beneficial effects of pigment epithelium-derived factor (PEDF), to which they are related, including anti-angiogenic, anti-tumorigenic, and immunomodulatory properties.
Pigment epithelium-derived factor (PEDF) also known as serpin F1 (SERPINF1), is a multifunctional secreted protein that has anti-angiogenic, anti-tumorigenic, immunomodulatory and neurotrophic functions. PEDF is being researched as a therapeutic candidate for treatment of such conditions as choroidal neovascularization, heart disease, and cancer. Previously, an 18 amino-acid PEDF peptide, P18, was shown to slow cancer growth and blocks ocular angiogenesis. We now report, more potent, practical and safe, modified peptides related to P18, which inhibit angiogenesis, directly kill ovarian cancer cells, and osteosarcoma cell, and exhibit other therapeutic properties. The modified peptides are uniquely suited chemically to be formulated as prodrugs where the latter are attached to particulate carriers, such as nanoparticles, via labile bonds which can be selected to control the rate of release of the modified peptides from the particulate carrier. The modified peptides also have amino acid substitutions that improve potency as compared with the naturally occurring PEDF amino acid sequence. In addition, we now show that these peptides also enhance resistance of the immune system to cancers, directly kill ovarian cancer cells and bone cancer cells, and protect sensitive normal cells, such as kidney cells, or retinal epithelium cells, from toxic effects of chemotherapy. The peptides also are shown to mitigate fibrotic processes and to have immune stimulatory activity.